Receptors for the major inhibitory neurotransmitter, gammaamino butyric acid (GABA), are divided into two main classes: GABAA receptors which are members of the ligand gated ion channel superfamily; and the GABAB receptors which are G-protein coupled receptors.
In a number of clinical conditions, hypoactivity of the inhibitory GABA system has been hypothesised as the underlying mechanism of the pathology in question. These conditions include epilepsy, anxiety, stress, sleep disorders and pain. However, although positive modulators of the GABAA receptor complex, such as benzodiazepines, in a number of circumstances are very effective, there is a general consensus that unselective benzodiazepines produce so many side effects that compounds substituting for presently used drugs are needed (Costa and Guidotto Trends Pharmacol. Sci. 1996, 17, 192-200).
The present invention provides non-steroidal and non-benzodiazepine compounds interacting directly with the recognition site at the GABAA receptor as agonists, which have beneficial effects in disease states relating to reduced neurostoroidal activation.
The diseases, including premenstrual syndrome, postnatal depression and post menopausal related dysphoric disorders, are significantly better treated with GABAA agonists than with benzodiazepines and neurosteroids which produce tolerance after short term treatment.
The potent GABA agonist 4,5,6,7-tetrahydroisoxazolo[5,4-c9]pyridin-3-ol (THIP) is disclosed in EP 000 338 B1 wherein a method of making the compound is also described. THIP is useful for treating sleep disorders which is disclosed in EP 840601 B1.
Definitions
The term “a” as used herein is intended to mean “one or more” or “at least one”, except where it is clear from the text that it means one.
The term “C1-4alkyl”, “C1-6alkyl”, or “C1-12alkyl” as used herein refers to a branched or unbranched alkyl group having from one to four, one to six, or one to twelve carbon atoms inclusive, respectively, including but not limited to methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methyl-2-propyl and 2-methyl-1-propyl.
The term “C1-6alkoxy”, or “C1-12alkoxy” as used herein designate such groups in which the C1-6-alkyl or C1-12-alkyl is as defined above and is linked via an oxygen, including but not limited to methoxy, ethoxy, 1-propoxy, 1-butoxy.
The term “C2-6alkenyl”, or “C2-12alkenyl” as used herein, respectively, designate such groups having from two to six carbon atoms, or two to twelve carbon atoms, including one double bond respectively, including but not limited to ethenyl, propenyl, and butenyl.
The term “C1-6alkylene” as used herein refers to a branched or unbranched alkylene group having from one to six carbon atoms inclusive, including but not limited to methylene, and ethylene.
The term “C3-8cycloalkyl” as used herein designates a monocyclic or bicyclic carbocycle having three to eight carbon atoms inclusive, including but not limited to cyclopropyl, cyclopentyl, and cyclohexyl.
The term “C3-8cycloalkenyl” as used herein designates a monocyclic or bicyclic carbocycle having three to eight carbon atoms inclusive and including one double bond.
The term “C1-12alkyl chloroformate” designate such groups in which the C1-12-alkyl, such as C1-6-alkyl, is as defined above and is the ester portion of a chloroformate, including but not limited to methyl chloroformate or ethyl chloroformate.
The term “acyl” as used herein refers to formyl, C1-6-alk(en/yn)ylcarbonyl, arylcarbonyl, aryl-C1-6-alk(en/yn)ylcarbonyl, C3-8-cycloalk(en)ylcarbonyl or a C3-8-cycloalk(en)yl-C1-6-alk(en/yn)yl-carbonyl group.
The expression C1-6-alk(en/yn)yl means a C1-6-alkyl, C2-6-alkenyl or a C2-6-alkynyl group. The expression C3-8-cycloalk(en)yl means a C3-8-cycloalkyl- or cycloalkenyl group.
The term “aryl” as used herein refers to carbocyclic, aromatic systems such as phenyl and naphtyl.
The term “heteroaryl” as used herein refers to 5- to 6-membered aromatic systems containing 1 to 5 carbon atoms and one or more heteroatoms selected from O, S or N, such as 5-membered monocyclic rings such as oxathiazoles, dioxazoles, dithiazoles, oxadiazoles, thiadiazoles, triazoles, isoxazoles, oxazoles, isothiazoles, thiazoles, imidazoles, pyrazoles, pyrroles, furan(s) or thiophene(s), e.g. 3H-1,2,3-oxathiazole, 1,3,2-oxathiazole, 1,3,2-dioxazole, 3H-1,2,3-dithiazole, 1,3,2-dithiazole, 1,2,3-oxadiazole, 1,2,3-thiadiazole, 1H-1,2,3-triazole, isoxazole, oxazole, isothiazole, thiazole, 1H-imidazole, 1H-pyrazole, 1H-pyrrole, furan or thiophene, or 6-membered monocyclic rings such as oxathiazines, dioxazines, dithiazines, oxadiazines, thiadiazines, triazines, oxazines, thiazines, pyrazines, pyridazines, pyrimidines, oxathiins, dioxins, dithiins, pyridines, pyrans or thiins, e.g. 1,2,3-oxathiazine, 1,2,4-oxathiazine, 1,2,5-oxathiazine, 1,4,2-oxathiazine, 1,4,3-oxathiazine, 1,2,3-dioxazine, 1,2,4-dioxazine, 4H-1,3,2-dioxazine, 1,4,2-dioxazine, 2H-1,5,2-dioxazine, 1,2,3-dithiazine, 1,2,4-dithiazine, 4H-1,3,2-dithiazine, 1,4,2-dithiazine, 2H-1,5,2-dithiazine, 2H-1,2,3-oxadiazine, 2H-1,2,4-oxadiazine, 2H-1,2,5-oxadiazine, 2H-1,2,6-oxadiazine, 2H-1,3,4-oxadiazine, 2H-1,2,3-thiadiazine, 2H-1,2,4-thiadiazine, 2H-1,2,5-thiadiazine, 2H-1,2,6-thiadiazine, 2H-1,3,4-thiadiazine, 1,2,3-triazine, 1,2,4-triazine, 2H-1,2-oxazine, 2H-1,3-oxazine, 2H-1,4-oxazine, 2H-1,2-thiazine, 2H-1,3-thiazine, 2H-1,4-thiazine, pyrazine, pyridazine, pyrimidine, 4H-1,3-oxathiin, 1,4-oxathiin, 4H-1,3-dioxin, 1,4-dioxin, 4H-1,3-dithiin, 1,4-dithiin, pyridine, 2H-pyran or 2H-thiin.
The term “acidification” as used herein means that an acid is added to the reaction mixture adjusting the pH to below pH 6.5.
The term “a leaving group” as used herein is a well-known expression to the skilled chemist, examples being halogens, such as Br, Cl, I, or mesylate or tosylate.
The term “a salt” as used herein is intended to mean any salt which a particular compound may form, and is usually intended to comprise acid addition salts, however, the compounds may also form other salts with bases, such as metal salts, eg. sodium salts, and ammonium salts, eg. salts of amines, such as triethylamine.
The term “an acid addition salt” as used herein is intended to mean any acid addition salt which a particular compound may form upon reaction of the compound with the acid in a solvent, as known to the skilled person in the art. Suitable examples are hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Other suitable examples are organic salts such as acetic, propionic, glycolic, oxalic, malonic, succinic, citric acid and the like.
The term “a mild reducing agent” as used herein is a well-known expression to the skilled chemist, reference is made to Brown, H. C; Krishnamurthy; Tetrahedron, 35, 1979, pp 567-607. Suitable examples are borohydrides.
The term “a nucleophile” as used herein is a well-known expression to the skilled chemist, reference is made to “Advanced Organic Chemistry” (3rd edition), Jerry March, Wiley-Interscience. The term “a soft nucleophile” as used herein is also described in “Advanced Organic Chemistry” (3rd edition), Jerry March, Wiley-Interscience. Suitable examples are Cl−, Br−, I−, or NC—S−.
The term “a dehydrating agent” as used herein is a well-known expression to the skilled chemist, and is intended to cover agents, such as thionylchloride, a chloroformate such as isobutyl chloroformate, or a carbodiimide such as DCI/DCC.